BACKGROUND: Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. METHODS AND RESULTS: This is an exploratory analysis of the TICH-2 (Tranexamic Acid in Intracerebral Hemorrhage-2) double-blind, randomized, placebo-controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre-ICH an-tiplatelet therapy, and 24-hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre-ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no-antiplatelet group. Pre-ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01– 1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32–1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25–2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62–0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41–0.91) with no significant interaction between pre-ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). CONCLUSIONS: Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional out-come. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.